Mechanisms linking primary biliary cholangitis and osteoporosis: A combined clinical and molecular analysis

Clinical Snapshot

Key Findings

• P Value: Not specified in abstract

• Effect Size: 36 shared differentially expressed genes identified

• Primary Outcome: PBC significantly increases risk of osteoporosis (Mendelian randomization)

• Nnt Or Sensitivity: VPS37C diagnostic performance: AUC >0.7 for both PBC and osteoporosis

• Confidence Interval: Not specified in abstract

Clinical Application

VPS37C testing would require specialized molecular diagnostics, currently research-grade Relevant to Australian gastroenterology and endocrinology practice; could inform PBS-funded bone density screening protocols for PBC patients and guide RACGP osteoporosis prevention guidelines Patients with PBC requiring osteoporosis screening, and those with unexplained osteoporosis requiring liver assessment

Abstract

Primary biliary cholangitis (PBC) is an immune-mediated cholestatic liver disease, and osteoporosis (OP) is a prevalent comorbidity that aggravates the disease burden of PBC patients. Although the co-occurrence of the 2 diseases has been widely observed, the underlying molecular mechanisms remain unclear. Herein, we evaluated the causal link between PBC and OP using Mendelian randomization (MR) and explored shared molecular mechanisms through bioinformatics and machine learning. We performed two-sample MR using genome-wide association study summary data for PBC and OP from the Integrative Epidemiology Unit database. Inverse-variance weighting was used as the primary MR method, with heterogeneity and horizontal pleiotropy tests performed to exclude potential biases. To explore shared molecular mechanisms, we analyzed transcriptomic datasets from the Gene Expression Omnibus database, identified comorbidity-associated differentially expressed genes, and applied multiple machine learning algorithms for biomarker screening and validation, combined with immune infiltration analysis. Our study showed that MR demonstrated that PBC significantly increases the risk of OP, while transcriptomic analysis identified 36 shared differentially expressed genes enriched in key biological pathways such as ribonucleic acid splicing and ubiquitin-mediated proteolysis. Furthermore, using 3 machine learning algorithms, we identified 12 PBC-specific and 4 OP-specific diagnostic genes, whose intersection revealed vacuolar protein sorting 37 homolog C (VPS37C) as a common diagnostic biomarker. In both diseases, VPS37C exhibited an area under the receiver operating characteristic curve value >0.7, demonstrating its robust predictive performance. In addition, VPS37C expression was found to be significantly correlated with the infiltration landscape of multiple immune cell types in both PBC and OP. This study identified VPS37C as a shared diagnostic gene linking PBC and OP, providing new insights into their comorbidity at both genetic and immune levels. Our findings further elucidate the molecular mechanisms underlying the comorbidity of PBC and OP, offer novel clues for understanding their pathogenesis, and highlight promising diagnostic and therapeutic targets for clinical application.

References

1. 1.Li, H., Guo, X., & Fan, Q. (2026). Mechanisms linking primary biliary cholangitis and osteoporosis: A combined clinical and molecular analysis. Medicine. https://doi.org/10.1136/gutjnl-2025-335611